Hemodialysis vascular access dysfunction is considered the single most important issue in the care of the patient with endstage renal failure. Yet our understanding of the pathogenesis of vascular access dysfunction is poor, to a large extent, because of the lack of availability of relevant models amenable to investigation. The PI has demonstrated that the venous limb of an aorto-caval fistula in the rat recapitulates changes seen in dysfunctional dialysis arteriovenous fistulae (AVFs): neointima formation, angiogenesis, thrombosis, smooth muscle cell proliferation, and matrix expansion; these changes in this model are preceded by massive upregulation of MCP-1 (monocyte chemoattractant protein-1), the latter being one of the most important chemokines in vascular injury, and an independent risk factor for the dysfunction of clinical AVFs. MCP-1 can be downregulated by mechanisms which include heme oxygenase-1 (HO-1), a heme-degrading, vasoprotective, and anti-inflammatory enzyme. This application examines the significance of MCP-1 upregulation in this AVF model, and whether HO-dependent strategies can inhibit MCP-1 and intimal hyperplasia. Aim I hypothesize that, and examine whether, clinically relevant mechanisms account for MCP-1 upregulation and intimal hyperplasia. Aim II hypothesizes that MCP-1 upregulation is a determinant of intimal hyperplasia, and employs strategies which interrupt MCP-1 or its receptor. Aim III determines whether HO induction or specific HO products/effectors inhibit MCP-1 expression and intimal hyperplasia. Aim IV hypothesizes that venous remodeling in the AVF involves MCP-1-dependent recruitment of circulating and bone marrow-derived cells, and analyzes the origin of cells in the AVF by immunophenotyping, bone marrow transplantation, and adoptive cell transfer. In aggregate, these studies will determine the basis for and the pathogenetic significance of such upregulation of MCP-1, and may suggest strategies for preventing dysfunction of AVFs.